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The surgical placement of dental implants is presently a common procedure performed by oral surgeons, periodontists, and general dentists. The surgery can be performed under local anesthesia and involves the incision of soft tissue to expose the underlying bone, preparation of the implant site using a specialized surgical drill, and.screwing the implant into bone using a specialized headpiece. Dental implant patients experience postoperative pain yet there are no studies in the literature which have evaluated the efficacy of analgesics in this patient population. The current pilot study will evaluate the analgesic effects and tolerability of a recently FDA-approved analgesic formulation of intranasal ketorolac (SPRIX®) in 25 patients who have 1 - 3 dental implants surgically placed. Patients will self administer the ketorolac nasal spray (one spray in each nostril, 31.5 mg total dose) when their postoperative pain reaches at least a moderate severity. Pain intensity and pain relief scores will then be recorded every 20 minutes for the first hour, at 1.5 and 2 hours and then hourly through 6 hours on a validated analgesic diary. Side effects will be recorded when and if they occur. Patients will then transition to a multi-dose phase where they will be allowed to dose with ketorolac as indicated in the package insert (up to 4 times per day for 5 days). Patients will record the time of each dose, a daily assessment of overall efficacy and side effects, and the use of any rescue medication (acetaminophen 650 mg) on a take home diary.
OBJECTIVES
To compare mean post-dose pain intensity scores at each time-point with the baseline pain intensity score during the initial 6-hour evaluation period.
To calculate the area under the 6-hour pain relief time action curve (TOTPAR-6) for intranasal ketorolac.
To calculate the percentage of subjects who reach a level of at least moderate pain by achieving a score of at least 40 mm on a 100 mm visual analog scale within 5 hours after the completion of surgery.
To determine the mean number of days of analgesic dosing in dental implant surgery patients when employing intranasal ketorolac as their pain medication.
To determine the number of patients taking rescue medication (acetaminophen 650 mg) and the mean number of rescue medication doses taken in dental implant surgery patients when employing intranasal ketorolac as their pain medication.
To determine the overall tolerability of intranasal ketorolac in dental implant surgery patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ketorolac nasal spray 31.5 mg | Experimental | Recommended dose according to package insert in 18 - 64 year olds for moderate to moderately severe pain. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketorolac Nasal Spray | Drug | 15.75 mg nasal spray delivery to each nostril no more than every six hours |
|
| Measure | Description | Time Frame |
|---|---|---|
| Comparison of Pain Intensity Scores at 20 Minutes With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period. | Pain intensity scores will be recorded by patient employing a standard 100 mm visual analog scale | 20 minutes post dose |
| Comparison of Pain Intensity Scores at 40 Minutes With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period. | VAS pain intensity score at 40 minutes post-dose | 40 minutes post dose |
| Comparison of Pain Intensity Scores at 60 Minutes With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | VAS pain intensity score 60 minutes after dosing. | 60 minutes post dose |
| Comparison of Pain Intensity Scores at 90 Minutes With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | 90 minutes post-dose | |
| Comparison of Pain Intensity Scores at 2 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | 2 Hours | |
| Comparison of Pain Intensity Scores at 3 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | 3 hours post-dose | |
| Comparison of Pain Intensity Scores at 4 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | 4 Hours post-dose | |
| Comparison of Pain Intensity Scores at 5 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period |
| Measure | Description | Time Frame |
|---|---|---|
| The Median Onset of First Perceptible Pain Relief of Intranasal Ketorolac in Dental Implant Surgery Patients | Data will be obtained employing the well-described double stop watch technique | Censored at 6 hours |
| Percentage of Subjects Who Reach a Level of at Least Moderate Pain by Achieving a Score of at Least 40 mm on a 100 mm Visual Analog Scale Within 5 Hours After the Completion of Surgery. |
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Inclusion Criteria:
Key Inclusion Criteria
Male or female between 18 and 64 years of age.
Must sign informed consent prior to initiation of any study procedures. The subject must be able to understand and agree to cooperate with study requirements.
BMI between 19 and 29 kg/m2.
Must require the surgical placement of 1 - 3 dental implants that are being placed in a one or two stage non-immediately loaded surgical procedure employing 2% lidocaine and/or 4% articaine with epinephrine and/or 3% mepivacaine plain for local anesthesia.
Females of child-bearing potential must have a negative urine pregnancy test at screening and immediately prior to the initiation of dental implant surgery and must have been using adequate means of birth control (abstinence, oral contraceptive steroids, intrauterine device (IUD), etc.) for at least one month prior to study entry and during the study.
In the opinion of the investigators the subject can safely tolerate ketorolac and acetaminophen.
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Exclusion Criteria:
Key Exclusion Criteria
Require the placement of more than 3 implants or require extensive bone grafting in addition to implant placement.
Need to administer anxiolytic/sedation drugs during surgery other than nitrous oxide/oxygen.
Need to administer the long acting local anesthetic bupivacaine with 1:200,000 epinephrine.
Implant(s) that are going to be immediately loaded on the day of surgery
Females that are pregnant or breast feeding
Allergies or hypersensitivity (aspirin sensitive asthma) to ketorolac, aspirin, ibuprofen, other NSAIDs, or acetaminophen.
History of gastrointestinal ulcers and/or bleeding.
On warfarin, dicumarol, clopidogrel or any other anticoagulant or antiplatelet therapy other than low dose (81 mg - 325 mg) aspirin.
Clinically significant kidney or liver disease where the intake of NSAIDs or acetaminophen would put the subject at undo risk.
Blood pressure greater than 160/95 at the time of screening or immediately before surgery.
Inflammation of the nasal mucosa or upper respiratory tract infection
Have ingested any analgesic agent within 48 hours of surgery.
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| Name | Affiliation | Role |
|---|---|---|
| Elliot V Hersh, DMD, MS, PhD | Univeristy of Pennsylvania School of Dental Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pennsylvania School of Dental Medicine | Philadelphia | Pennsylvania | 19104-6030 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17274712 | Background | Al-Khabbaz AK, Griffin TJ, Al-Shammari KF. Assessment of pain associated with the surgical placement of dental implants. J Periodontol. 2007 Feb;78(2):239-46. doi: 10.1902/jop.2007.060032. | |
| 15476903 | Background | Hersh EV, Levin LM, Adamson D, Christensen S, Kiersch TA, Noveck R, Watson G 2nd, Lyon JA. Dose-ranging analgesic study of Prosorb diclofenac potassium in postsurgical dental pain. Clin Ther. 2004 Aug;26(8):1215-27. doi: 10.1016/s0149-2918(04)80033-x. |
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Subjects not experiencing moderate pain (at least 40 mm on the pain intensity VAS and moderate or severe pain on the 4-point categorical scale) within 4 hours of surgery were not dosed with ketorolac. Of the 28 enrolled subjects, 25 (89%) achieved at least moderate pain and were dosed.
Consecutive patients in PENN periodontal clinic or faculty practice requiring 1 to 3 dental implants employing lidocaine with epinephrine for anesthesia without significant bone augmentation
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| ID | Title | Description |
|---|---|---|
| FG000 | Ketorolac Nasal Spray 31.5 mg (SPRIX) | Recommended dose according to package insert in 18 - 64 year olds for moderate to moderately severe pain. Ketorolac Tromethamine Nasal Spray: 15.75 mg nasal spray delivery to each nostril no more than every six hours |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Pilot Study. No power analysis performed.
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| ID | Title | Description |
|---|---|---|
| BG000 | Ketorolac Nasal Spray 31.5 mg (SPRIX) | Recommended dose according to package insert in 18 - 64 year olds for moderate to moderately severe pain. Ketorolac Tromethamine Nasal Spray: 15.75 mg nasal spray delivery to each nostril no more than every six hours |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Secondary | The Median Onset of First Perceptible Pain Relief of Intranasal Ketorolac in Dental Implant Surgery Patients | Data will be obtained employing the well-described double stop watch technique | Posted | Median | 95% Confidence Interval | seconds | Censored at 6 hours |
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5 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ketorolac Nasal Spray 31.5 mg (SPRIX) | Recommended dose according to package insert in 18 - 64 year olds for moderate to moderately severe pain. Ketorolac Tromethamine Nasal Spray: 15.75 mg nasal spray delivery to each nostril no more than every six hours |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasal burning or stinging | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Transient nasal burning on dosing in 9/25 (36%) of subjects |
The major weakness of this study was its open-label design and lack of a placebo control and an active comparator drug. The study was also not powered to determine differences between the sites of implant placement and the number of implants placed.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Elliot V Hersh DMD, MS, PhD Professor of Pharmacology | Univeristy of Pennsylvania School of Dental Medicine | 215-898-9686 | evhersh@pobox.upenn.edu |
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| ID | Term |
|---|---|
| D059787 | Acute Pain |
| D014098 | Toothache |
| ID | Term |
|---|---|
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| 5 Hours post-dose |
| Comparison of Pain Intensity Scores at 6 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | 6 Hours post-dose |
| Up to 5 hours after last suture is placed |
| Most Frequent Number of Days of Analgesic Dosing in Dental Implant Surgery Patients When Employing Intranasal Ketorolac as Their Pain Medication. | Self explanatory | Up to 5 days |
| Median Onset of Meaningful Pain Relief | Measure obtained using recognized double-stop watch technique. Patient is asked to depress the second stop watch when pain relief is meaningful to them. Each patient decides what meaningful relief is for them. | At time of depressing meaningful relief stopwatch up to 6 hours. |
| 24564610 | Result | Bockow R, Korostoff J, Pinto A, Hutcheson M, Secreto SA, Bodner L, Hersh EV. Characterization and treatment of postsurgical dental implant pain employing intranasal ketorolac. Compend Contin Educ Dent. 2013 Sep;34(8):570-6. |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| pain intensity on 100 mm visual analog scale (VAS). 0=No pain 100=worst possible pain | Mean | Standard Deviation | units on a scale |
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| Primary | Comparison of Pain Intensity Scores at 20 Minutes With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period. | Pain intensity scores will be recorded by patient employing a standard 100 mm visual analog scale | Posted | Mean | Standard Error | millimeters | 20 minutes post dose |
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| Secondary | Percentage of Subjects Who Reach a Level of at Least Moderate Pain by Achieving a Score of at Least 40 mm on a 100 mm Visual Analog Scale Within 5 Hours After the Completion of Surgery. | All subjects (regardless of pain intensity) receiving one to three dental implants | Posted | Number | percentage of participants | Up to 5 hours after last suture is placed |
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| Secondary | Most Frequent Number of Days of Analgesic Dosing in Dental Implant Surgery Patients When Employing Intranasal Ketorolac as Their Pain Medication. | Self explanatory | Posted | Number | days | Up to 5 days |
|
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|
| Secondary | Median Onset of Meaningful Pain Relief | Measure obtained using recognized double-stop watch technique. Patient is asked to depress the second stop watch when pain relief is meaningful to them. Each patient decides what meaningful relief is for them. | Posted | Median | 95% Confidence Interval | seconds | At time of depressing meaningful relief stopwatch up to 6 hours. |
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| Primary | Comparison of Pain Intensity Scores at 40 Minutes With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period. | VAS pain intensity score at 40 minutes post-dose | Posted | Mean | Standard Error | millimeters | 40 minutes post dose |
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| Primary | Comparison of Pain Intensity Scores at 60 Minutes With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | VAS pain intensity score 60 minutes after dosing. | Posted | Mean | Standard Error | millimeters | 60 minutes post dose |
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| Primary | Comparison of Pain Intensity Scores at 90 Minutes With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | Posted | Mean | Standard Error | millimeters | 90 minutes post-dose |
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| Primary | Comparison of Pain Intensity Scores at 2 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | Posted | Mean | Standard Error | millimeters | 2 Hours |
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| Primary | Comparison of Pain Intensity Scores at 3 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | Posted | Mean | Standard Error | millimeters | 3 hours post-dose |
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| Primary | Comparison of Pain Intensity Scores at 4 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | Posted | Mean | Standard Error | millimeters | 4 Hours post-dose |
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| Primary | Comparison of Pain Intensity Scores at 5 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | Posted | Mean | Standard Error | millimeters | 5 Hours post-dose |
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| Primary | Comparison of Pain Intensity Scores at 6 Hours With the Baseline Pain Intensity Score During the Initial 6-hour Evaluation Period | Posted | Mean | Standard Error | millimeters | 6 Hours post-dose |
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| 0 |
| 25 |
| 14 |
| 25 |
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| Throat burning | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Transient throat burning on dosing 3/25 subjects (12%) |
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| Headache | Nervous system disorders | Non-systematic Assessment | 3 of 25 (12%) reported headache sometime during 5 day evaluation period |
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| Sneezing | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Sneezing on dosing 2/25 (8%) |
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| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
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| Difficulty breathing sensation | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Transient difficulty breathing sensation immediately after dosing |
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| Ears popping sensation | Ear and labyrinth disorders | Non-systematic Assessment | Transient immediately after dosing |
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| Perspiring | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Runny nose | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Watery eyes | Eye disorders | Non-systematic Assessment |
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| D014076 | Tooth Diseases |
| D009057 | Stomatognathic Diseases |
| D005157 | Facial Pain |